Is CIT p.Arg2000His (c.5999G>A) pathogenic?

CIT p.Arg2000His (c.5999G>A) is classified Uncertain significance in CIT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-25). AlphaMissense: likely pathogenic (0.5684); Ultra-rare (popmax 0.0199%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIT p.Arg2000His (c.5999G>A)?

CIT p.Arg2000His (c.5999G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CIT p.Arg2000His (c.5999G>A) in the general population?

CIT p.Arg2000His (c.5999G>A) is ultra-rare (popmax 0.0199%, nfe) (gnomAD).

What do computational predictors say about CIT p.Arg2000His (c.5999G>A)?

AlphaMissense predicts likely pathogenic (score 0.5684) — an in-silico prediction, not a clinical call.

CIT p.Arg2000His

c.5999G>A · rs200787337 · VCV1254402

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5684	likely pathogenic
REVEL	0.366	indeterminate
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 32 kb · p 1.5e-18 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1958H vs ClinVar R2000H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0199% European (non-Finnish) · 234/1,178,284 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.0168% 269/1,597,300 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.039%	2,565
European (non-Finnish)grpmax	0.0199%	5,035
Remaining individualsnot grpmax-eligible	0.0193%	5,181
African / African-American	0.00267%	37,434
South Asian	0.00111%	90,378

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CIT
Protein: p.Arg2000His
Coding: c.5999G>A
MANE Select: NM_001206999
dbSNP: rs200787337
Type: single nucleotide variant
Location: chr12:119690338 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75

Full CIT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIT p.Arg1178Ter Pathogenic ★★ same condition
CIT c.4168+5G>A Uncertain significance ★★ same condition
CIT p.Ala1527Val Uncertain significance ★★ ⚠ same condition
CIT p.Ala495Ser Uncertain significance ★★ ⚠ same condition
CIT p.Ala8Val Uncertain significance ★★ ⚠ same condition
CIT p.Arg100Gly Uncertain significance ★★ ⚠ same condition
CIT p.Arg1469Cys Uncertain significance ★★ ⚠ same condition
CIT p.Arg1861Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cit-p-arg2000his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown